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Final Exam Study Guide

by: Madi Raines

Final Exam Study Guide CH 461

Marketplace > University of Oregon > Chemistry > CH 461 > Final Exam Study Guide
Madi Raines
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Covers redox reactions and metabolism, including glucose, fatty acids, cholesterol, and nucleotide synthesis.
Kenneth Prehoda
Study Guide
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This 30 page Study Guide was uploaded by Madi Raines on Monday May 16, 2016. The Study Guide belongs to CH 461 at University of Oregon taught by Kenneth Prehoda in Fall 2015. Since its upload, it has received 15 views. For similar materials see Biochemistry in Chemistry at University of Oregon.


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Date Created: 05/16/16
Biochemistry Final Exam Study Guide Equilibria, Thermodynamics, and Redox Reactions 1. Understand basic chemical equilibria: K eqG’, G’ a. Keq equilibrium constant i. Reaction quotient at equilibrium b. G’: change in Gibb’s free energy at standard state c. G’: change in Gibb’s free energy not under cellular conditions 2. Be able to solve free energy equations 3. Understand redox reactions and know how to calculate G’ or G’ for redox reactions a. Redox reactions are coupled reactions with transfer of electrons from donor to acceptor b. Oxidation is loss, reduction is gain c. Can separate oxidation reactions into oxidative and reductive half reactions i. Find redox values in table ii. Flip sign of oxidation reaction iii. Add, then plug into G’= -nFE’ iv. Then calculate G’ using G’= -nFE’ + RTlnQ Enzymes, Membranes, and Membrane Transport 1. Know the relationship between ∆G°’, ∆G’, ∆G=, and ∆∆G= , activation energy, rate enhancement, reaction rates and enzymes as catalysts, and the general role of cofactors/coenzymes in enzyme catalysis. a. Rate of reactions are limited by the activation energy barrier b. Rate constant is related to ∆G=/ i. K=A*e(-∆G=//RT) c. Enzymes do not effect ∆G, only the rate of reaction d. Coenzymes i. Organic non-protein molecules that bind with the protein molecule to form the active enzyme (holoenzyme) ii. Bind to enzymes active site 2. Know generally the types of enzymes, the types of reactions they catalyze, and their coenzymes a. Kinases i. Adds phosphate groups by phosphorylation ii. Coenzyme: None b. Dehydrogenases i. Oxidizes a substrate by a reduction reaction, transfers hydrogens from substrate to an acceptor ii. Coenzymes: 1. FAD: formation of double bonds 2. NAD+ or NADP+ 3. Lipoamide/Lipoic Acid for pyruvate DH or alphaketo DH 4. CoA for pyruvate DH c. Isomerases i. Convert a molecule from one isomer to another ii. Coenzyme: None d. Epimerases i. Catalyze inversion of stereochemistry, convert epimers (only differ at one stereochemical center) e. Phosphatases i. Removes phosphate group to produce phosphate ion and a molecule with a free hydroxyl group ii. Coenzymes: none f. Aldolase i. C-C cleavage reactions, active site lysine residue forms Schiff base with carbonyl carbon ii. Coenzyme: none g. Transaldolase: i. C3 + C7  C6 + C4 : 3 C transfer ii. Use lysine side chain to form Schiff base intermediate iii. Coenzyme: None h. Transketolase i. 2 C transfer ii. C5 + C4  C6 + C3 iii. C5 + C5  C7 + C3 iv. Coenzyme: TPP i. Carboxylase i. Addition of carboxyl group ii. Coenzyme: Biotin j. Decarboxylase i. Removes carboxyl group and releases CO2 ii. Coenzyme: None k. Synthetases i. Links together two molecules ii. Usually uses energy derived from ATP hydrolysis iii. Coenzyme: ???? 3. Know ways to change an enzyme’s activity a. Substrate levels b. Allosteric effectors c. Covalent modification d. Competitive inhibition 4. Understand the physical characteristics of phospholipid bilayers, and the dynamics of membranes a. Phospholipid bilayers: i. Phospholipids with two fatty acid chains are cylindrical and preferentially form flat bilayers ii. Stabilized by head group:H2O interactions iii. Center of bilayer: very hydrophobic, essentially an organic phase iv. Order/disorder phase transition: well-defined phase transition for simple bilayers v. Melting temperature increases with increase in FA chain length and degree of saturation 1. Fluid phase: above Tm a. Disordered b. High mobility c. 2D liquid 2. Gel-like phase: below Tm a. Ordered b. Limited mobility c. Highly ordered packing vi. Disordered-ordered transition is highly cooperative vii. Addition of cholesterol in bilayer decreases membrane fluidity and can eliminate the phase transition viii. Lipid motion in bilayers: 1. Flip-flop: extremely slow 2. Lateral diffusion: very fast a. Use FRAP to measure lateral diffusion b. Dynamics of membranes i. Flippases are required to flip phospholipid across bilayer and are only in the ER 5. Understand how hydropathy plots can provide insights into protein structure and topology a. Window size: the window is the # of amino acids over which the hydrophobic index is summed b. Soluble globular proteins: maximum stretch of hydrophobic aa’s is 7-9, so use a window of 7-9 c. Integral membrane proteins: TMD is alpha-helical stretch of 18- 20 hydrophobic aa’s, use window of 18-20 6. Understand membrane transport a. Active vs. Passive i. Passive 1. No energy needed 2. Down a concentration gradient from high to low concentration 3. Permeability coefficient is proportional to hydrophobicity 4. Not saturable ii. Active 1. Requires ATP 2. Usually against a concentration gradient 3. Saturable because enzyme transporter involved b. Uniporters: i. Ion channel or carrier-proteins ii. Gramicidin or valinomycin c. Antiporters i. Transports two different molecules across a lipid membrane in opposite directions ii. G’=RTlnQ 1. If Q < 1, then G’ is negative 2. When G’ is negative, rxn spontaneous left to right iii. If transported species carry a charge, we have to consider electric potential term 1. G’= RTlnQ + zF(psi) d. Secondary active transport i. Na-Glucose Symporter ii. Drives Glc up concentration gradient, down Na concentration and electrical gradient in intestinal cells 7. Understand the logic of the different properties of the various glucose transporters a. Glut1 i. Blood brain barrier ii. Always saturated in the cell b. Glut 2 i. Liver/kidney cells ii. Never saturated in the cell iii. Glc uptake is proportional to blood glucose concentration c. Glut4 i. Muscle/Fat ii. Number of Glut4 transporters at PM is dependent on [Insulin]/[Glucagon] ratio iii. Insulin binding to insulin receptor signals intracellular Glut4 to PM d. Na+/Glc Symporter i. Glucose uptake from small intestine into brush border epithelial cells by secondary active transport ii. Makes use of [Na+] gradient and also psi which is negative inside iii. Drives Glc transport up its concentration gradient iv. Glc transport is favored when [Na+] and [Glc] is greater on the outside of the cell 8. Understand the driving force for membrane transport a. Concentration gradients b. psi c. ATP hydrolysis Sugars, Glycolysis, Gluconeogenesis, Glycogen Metabolism 1. Understand the terms: a. Reducing: i. Can be oxidized and is able to reduce another substance without having to be hydrolyzed first b. Non-reducing: i. Unable to be oxidized and cannot reduce other substances c. Chiral: i. Structure and mirror image are non-superimposable d. Prochiral i. Molecules that can be converted from achiral to chiral in one step e. Epimer i. Two isomers that differ at one stereogenic center f. Anomer i. Stereoisomers of cyclic sugars that differ in the configuration at the anomeric carbon ii. Either alpha or beta anomers 2. Understand the role of the hexose monophosphate pool in cellular metabolism a. Fructose-6-P i. Feeds into glycolysis to produce Fru-1,6-BP through PFK-1 to produce PEP ii. PEP is converted to pyruvate and feeds into TCA cycle by acetyl-coA iii. Acetyl-coA either produces fatty acids, or CO2 and NADH/FADH through the TCA cycle b. Glc-6-P i. Feeds into PPP to produce Fru-6-P and GAP, or ribose-5-P depending on whether the cell is dividing c. G-1-P i. Glycogen synthesis d. Steps leading out of HMP are the flux control steps for each pathway 3. Understand the logic and energetics of glycolysis, as well as the aerobic and anaerobic fates of pyruvate a. Energetics of glycolysis i. Investment phase 1. Prepares Glc to be cleaved 2. Cleave to yield 2 trioses 3. Costs 2 ATP per Glc ii. Payoff phase 1. Oxidation/phosphorylation: yields 2 NADH 2. 2 substrate level phosphorylations: 2 x 2 ATP rxns = 4 ATP iii. One Glc produces 2 pyruvates b. Fate of pyruvate i. Anaerobic: 1. Reduction to lactate by lactate DH 2. Consumes NADH produced during glycolysis 3. Maintains oxidized NAD+ ii. Aerobic: 1. Converted to acetyl-coA 2. Loss of CO2 and NADH is reoxidized by ETC iii. Balanced fermentation: 1. Glc  2 lactate + 2 ATP with reoxidation of NADH 4. Understand the role of NAD+/NADH and NADP+/NADPH in metabolism a. NAD+/NADH i. Key for donating and accepting electrons during oxidation reactions ii. Transfers electrons generated by catabolism to the ETC iii. Ratio kept high in the cell b. NADP+/NADPH i. Used in mostly anabolic reactions ii. Ratio kept low in the cell 5. Understand the regulation of PFK-1 and FBPase-1, as well as pyruvate kinase a. Regulation of PFK-1 and FBPase-1 i. By F-2,6-BP: 1. Produced by PFK-2 2. Most potent deinhibitor of PFK-1: allosteric effector 3. Increased [F-2,6-BP]  increased glycolytic flux 4. Levels are hormonally controlled 5. Inhibits FBPase-1: further increases glycolytic flux 6. In liver cells: glycogen breakdown is coordinated with decreased glycolysis a. Glucagon stimulates cAMP, which inhibits PFK- 2, reducing F-2,6-BP levels 7. In muscle cells: glycogen breakdown is coordinated with increased glycolysis a. Glucagon stimulates cAMP which inhibits FBPase-2 and increases Fru-2,6-BP ii. By ATP/AMP: 1. AMP is a deinhibitor of PFK-1 a. Stabilizes the R state 2. AMP competes with ATP for PFK-1 allosteric binding site 3. AMP decreases Km of PFK-1 for F-6-P 4. Increased glycolysis when ratio of [ATP]/[AMP] low b. Regulation of pyruvate kinase i. F-1,6-BP activates pyruvate kinase 1. Helps ensure that F-1,6-BP made in flux controlling step will make it all the way to pyruvate ii. In liver cells only: 1. Activated PKA (cAMP activated) phosphorylates PK 2. Phospho-PK is inhibited and stimulates gluconeogenesis 6. Understand the logic and benefit to the cell of substrate/futile cycles and flux-controlling steps a. Substrate/futile cycles i. Increase sensitivity to equilibrium changes ii. Important for regulating the heat generation and energy loss iii. Allows two metabolic processes to occur simultaneously with no net loss of energy b. Flux-controlling steps i. Important for regulation of metabolic pathways under different cellular conditions 7. Understand the unique role of the liver in glucose homeostasis, and the effects of glycogen storage diseases a. Role of liver in glucose homeostasis i. Continuous uptake of blood Glc by Glut2 ii. Glycolysis produces Glc to transport to blood iii. Glycolysis inhibited by high glucagon and epinephrine iv. Glycolysis and gluconeogenesis inhibited by insulin signaling b. Effects of glycogen storage diseases i. Glc-6-phosphatase 1. Accumulation of glycogen  low blood Glc 2. Increased intracellular [Glc-6-P] a. Glc-6-P inhibits glycogen phosphorylase b. Glc-6-P activates glycogen synthase ii. Branching enzyme 1. Accumulation of very long unbranched glycogen chains (low solubility) 2. Liver dysfunction by 4 years iii. Phosphorylases: 1. Type V: muscle phosphorylase a. Inability to mobilize muscle glycogen, painful mucle cramps with exertion 2. Type VI: Liver phosphorylase a. Accumulation of glycogen leading to low blood glucose iv. Glycogen synthase 1. Results in low levels of glycogen 2. Hyperglycemia after eating (Glc  glycogen) 3. Hypoglycemia at other times a. No glycogen because only gluconeogenesis can take place v. Muscle PFK-1 1. Glc-6-P accumulates a. Activates glycogen synthase b. Inactivates glycogen phosphorylase 2. Glycolysis cannot keep up with ATP demand 8. Understand the kinase/phosphatase cascades that control glycogen metabolism and glycolysis/gluconeogenesis a. Glycogen phosphorylase i. Activation: phosphorylation and ATMP ii. Signal: 1. Liver: glucagon and epinephrine 2. Muscle: epinephrine iii. Inactivation: dephosphorylation, Glc-6-P, ATP b. Glycogen synthase i. Activation: dephosphorylation, Glc-6-P, ATP ii. Inactivation: phosphorylation, AMP iii. Signal: 1. Liver: glucagon and epinephrine 2. Muscle: epinephrine c. Second messenger system i. cAMP activated by adenylate cyclase 1. Second messenger amplification ii. cAMP activates PKA d. PPP-1 signals glycogen synthesis by dephosphorylating both phosphorylase and synthase i. Signaled by insulin which also signals Glut4 Glc transporters to PM in high blood Glc 9. Understand the goal, the flux-controlling step, the regulation, and the phases of glycolysis, gluconeogenesis, and glycogen metabolism, as well as the key steps (and bypass steps) in these pathways a. Glycolysis i. Goal: break down Glc to produce pyruvate and ATP ii. Flux-controlling step: 1. Conversion of Fru-6-P to Fru-1,6-BP by PFK-1 iii. Regulation: 1. PFK-1 activated by Fru-2,6-BP 2. Glycolysis activated in liver cells when: a. High blood glucose b. High glucagon 3. Glycolysis activated in muscle cells when: a. High epinephrine/adrenaline iv. Phases: 1. Preparatory/Investment Phase: a. Prepares Glc to be cleaved b. Cleave to yield 2 trioses c. Costs 2 ATP per Glc 2. Payoff phase: a. Oxidation/phosphorylation produces 2 NADH b. 2 substrate level phosphorylations produces 4 ATP v. Key steps: ????? b. Gluconeogenesis i. Goal: produce new Glc in liver 1. Precursors: a. Lactate b. Pyruvate c. Most amino acids d. TCA cyle intermediates 2. Must make PEP to make Glc ii. Flux-controlling step: 1. Fru-6-P to Fru-1,6-BP substrate cycle 2. Pyruvate to PEP substrate cycle also exhibits regulation a. Two step bypass reaction iii. Regulation: 1. Fru-1,6-BP  F-6-P a. FBPase-2 inhibited by F-2,6-BP 2. Pyruvate to PEP substrate cycle a. Need two ATPs to bypass PK b. Pyruvate carboxylase converts pyruvate to OAA and is activated acetyl-coA c. PEPCK converts OAA to PEP and production of PEPCK stimulated by glucagon iv. Transfer of OAA out of mito matrix 1. Pyruvate transported into mitochondrial matrix 2. Carboxylated to form OAA 3. OAA is either reduced to malate or decarboxylated to PEP 4. PEP or malate transferred to cytosol 5. Malate would then we oxidized to OAA, then decarboxylated to PEP 6. Malate-Aspartate Shuttle a. Transfer of NADH reducing equivalents to cytosol b. In liver cells in low blood glucose: i. OAA  malate ii. Malate  cytosol iii. Malate reoxidized to OAA v. Phases and Steps: 1. Conversion of pyruvate to OAA a. Pyruvate carboxylase 2. Decarboxylation of OAA to PEP a. PEPCK c. Glycogen metabolism i. Goal: Breakdown and release of Glc ii. Flux-control step 1. Glycogen phosphorylase iii. Regulation: 1. Glycogen phosphorylase activated by phosphorylation and AMP a. Signal: i. Liver: glucagon and epinephrine ii. Muscle: epinephrine 2. Glycogen phosphorylase inactivated by dephosphorylation, ATP, and Glc-6-P 3. Phosphorylation cascade with cAMP and PKA iv. Key steps: 1. Glycogen phosphorylase 2. Glycogen debranching enzyme a. Phosphorylase cannot get closer than 4 units to a limit branch 10. Understand how glycolysis, gluconeogenesis, and glycogen metabolism (and their regulation) are integrated a. Glycogen metabolism breaks down glycogen to Glu-1-P b. Glu-1-P is then converted to Glu-6-P and Fru-6-P (HMP) c. Fru-6-P is precursor to glycolysis d. Gluconeogenesis converts pyruvate, the end product of glycolysis, to Glc. Citric Acid Cycle, Electron Transport Chain, and Oxidative Phosphorylation 1. Understand the mechanism of pyruvate dehydrogenase, and the roles for its coenzymes a. Mechanism of pyruvate dehydrogenase i. 3 enzyme activities in mitochondrial matrix 1. E1: pyruvate dehydrogenase 2. E2: dihydrolipolyl transacetylase 3. E3: dihydrolipolyl dehydrogenase ii. Five step reaction 1. TPP attack on pyruvate a. Alpha-keto acid decarboxylations b. Forms TPP:hydroxyethyl intermediate 2. Lipoic acid attached to lysine a. Lipoic acid receives acetyl group from TPP b. Lipoid acid extends 14 angstroms from lysine 3. Transfer of acetyl group to Coenzyme A a. CoA: pantothenic acid attached to ADP b. E2 catalyzes the transfer of the acetyl group to CoA 4. E3 reoxidizes dihydrolipoamide a. Disulfide group and a tightly bound FAD 5. Reduced E3 is reoxidized by NAD+ iii. Coenzymes: 1. TPP: decarboxylates pyruvate 2. Lipoic acid: accepts hydroxyethyl-TPP carbanion as an acetyl group 3. CoA: accepts acetyl group from lipoamide 4. FAD: reduced by lipoamide 5. NAD+: Reduced by FADH 2. Understand the overall scheme of the TCA cycle, and the products and types of enzymes of the cycle a. Goal: conserve free energy of acetate oxidation to CO2 and produce ATP b. 2CO2 per 1 Acetyl-CoA c. Produces reducing equivalents i. 3 NADH ii. 1 FADH2 d. Steps i. Condensation of acetyl-coA with OAA to from citrate 1. Citrate synthase ii. Formation of isocitrate by aconitase 1. No chiral carbons  1 chiral iii. Formation of alpha-ketogularate by isocitrate dehydrogenase 1. Cofactor: NAD+ iv. Formation of succinyl-coA by alpha-ketoglutarate dehydrogenase 1. Cofactor: NAD+ v. Formation of succinate by succinyl-coA synthetase vi. Formation of fumarate by succinate dehydrogenase 1. Cofactor: FAD+ 2. Double bond formation vii. Formation of malate by fumarase 1. Hydration of double bond viii. Formation of OAA by malate dehydrogenase 1. Cofactor: NAD+ e. Products: i. NADH and FADH reoxidized by ETC ii. 2 CO2 3. Understand the amphibolic nature of the citric acid cycle and its relevance to metabolism a. Amphibolic: i. Catabolic: oxidation/degradation cycle ii. Anabolic: TCA intermediates used in biosynthetic pathways b. Contains many anaplerotic reactions: cycle filling i. Particularly relevant to gluconeogenesis ii. Replenish TCA cycle intermediates 4. Understand the glyoxylate cycle as well as the key site of citric acid cycle regulation, their effectors, and how regulation the cycle is integrated and coordinated a. Glyoxylate cycle i. Anaplerotic ii. Two enzymes allow bypass of 5 TCA cycle steps 1. Isocitrate lyase converts isocitrate to succinate and glyoxylate 2. Malate synthase combines glyoxylate and acetyl-coA to l-matae iii. Pathway bypasses decarboxylation steps b. Key site of TCA cycle regulation i. NADH is global regulator of cycle 1. Inhibits Acetyl-coA + OAA  citrate ii. Substrate limiting 1. [Acetyl-coA] and [OAA] in mitochondria are below Km for citrate synthase c. How the TCA cycle is integrated and coordinated 5. Understand the roles of complex I through V in the ETC and the entry of electrons from NADH and FADH a. Transfer of cytosolic NADH i. Malate-Aspartate shuttle 1. Malate into mito matrix 2. Electrons from NADH into the mitochondrial matrix a. Liver: high blood glc b. Muscle: Aerobic c. Nerve cells: always 3. What drives cycle: mass action 4. OAA  malate  mito matrix  OAA ii. Glycerophosphate shuttle 1. Glycerol-3-phosphate DH oxidizes NADH to NAD+ 2. Electrons passed to glycerol-3-phosphate 3. Flavoprotein DH transfers electrons from glycerol-3- phosphate to FADH in inner mitochondrial membrane b. Complex I i. NADH electrons enter, is oxidized ii. NADH-CoQ reductase iii. NADH oxidized, CoQ reduced iv. FMN and CoQ as cofactors c. Complex II i. FADH2 electrons enter ii. Succinate dehydrogenase iii. FAD + succinate  fumarate + FADH2 iv. FADH2 + CoQ (oxid)  FAD + CoQ (red) d. Complex III i. Cytochrome bc1 complex ii. CoQ(red) + cytochrome c (Fe3+)  CoQ (oxid) + Cyto c (Fe2+) e. Complex IV i. Cytochrome c oxidase ii. 2Cyto c (Fe2+) + 1/2O2  Cyto c (Fe3+) + H2O 6. Understand the redox-loop and proton pump models of integration ETC with H+ translocation a. Redox-loop model i. Diffusible e-/H+ carrier (CoQ) 1. Electrons and H+ are accepted on one side of the membrane and donated on the other ii. Q cycle iii. Complex III and Complex I 1. 2 H+ translocated/1 e- 2. 4 H+/2e- through Complex III b. Proton pump mechanism i. No diffusible redox center ii. H+ translocating channel in cytochrome c oxidase 1. Conformational change in cytochrome oxidase during oxidation/reduction a. 2H+/2e- iii. Cytochrome c oxidase: Complex IV 1. O2 + 4e- + 4H+  2H2O 7. Understand how oxidative phosphorylation is controlled and the overall integration of control of the entire pathway of glucose oxidation and the aerobic vs anaerobic production of ATP a. Control of oxidative phosphorylation i. Acceptor control ii. [ADP] in mito matrix is often rate limiting for ox-phos 1. [ATP]/[ADP] ratio high a. Ox-phos slows ([NADH] builds up) b. TCA cycle flux slows/stops (Complex II remains reduced) c. Glycolysis flux slows 2. [ATP]/[ADP] ratio low: a. Ox-phos increases (decrease of [NADH]) b. TCA cycle increases c. Glycolysis flux slows b. Aerobic vs. anaerobic production of ATP i. Aerobic: 32 ATP from glycolysis to TCA cycle ii. Anaerobic: 4 ATP produced just from glycolysis 8. Understand the chemiosmotic hypothesis, the energetics of oxidative phosphorylation, how the PMF is coupled to ATP synthesis, and how to calculate the PMF. a. Chemiosmotic hypothesis: i. The action of ATP synthase is couple with a proton gradient ii. Proton gradient causes PMF that allows ATP synthase to convert ADP  ATP iii. Protons are pumped into integral membrane space, and are then pumped out into the mitochondrial matrix b. The energetics of oxidative phosphorylation c. How the PMF is coupled to ATP synthesis i. H+ translocation causes rotation of gamma subunit ii. Rotation of gamma subunit deforms catalytic sites (F 0 rotates relative to 1 ) iii. A subunit has two half channels for H+ iv. C subunit must pick up a H+ before rotating into bilayer v. One H+ is translocated for each c subunit in 360 rotation d. How to calculate the PMF i. G’=5.7pH + nF 9. Understand the function of ATP synthase and the relationship between H+ flow and ATP synthesis 10. Understand the tight coupling of e- flow through the ETC and ATP synthesis, and the effect of uncouplers. a. 12 H+ removed from matrix every time 2 e- pass from NADH to O2 b. If ATP synthesis stops, e- transport stops c. Coupled through the PMF d. Uncouplers: i. DNP 1. Dissipates H+ gradient 2. Crosses IMM to matrix, H+ dissociates in high pH matrix 3. H+ flow bypasses ATP synthase 4. E- transport proceeds independent of ATP synthesis ii. UCP1 1. Brown adipose tissue 2. Dissipates H+ gradient to bypass ATP synthase 3. Hormonally controlled: norepinephrine 4. Thermogenesis instead of ATP synthesis 5. UCP2-UCP5 found in mitochondria of regular adipose and other tissues 11. Understand how electrons from cytosolic NADH enter the ETC a. Malate aspartate shuttle i. Malate into mito matrix 1. Liver: low blood glucose 2. Muscle: aerobic b. Glycerophosphate shuttle: i. Transfer of electrons from NADH in cytosol through glycerol-3-phosphate ii. To FADH, and eventually to ETC 12. Understand the molecular basis for thermogenesis via uncoupler proteins; which cell types and how a. UCP1 discovered in BAT i. Norepenephrine signal dissipation of H+ gradient ii. Thermogenesis instead of ATP synthesis Pentose Phosphate Pathway and Photosynthesis 1. Understand the flux control step, regulation, and phases of the PPP a. Goals: i. Generate NADPH ii. Synthesis of nucleotide precursors (ribose-5-P) b. Flux control step: i. First step out of HMP ii. Glc-6-P + NADP+  6-phosphogluconolactone + NADPH c. Regulation i. Rate determined by ratio of NADP+/NADPH and whether the cell is replicating or not d. Phases i. Oxidation of Glc-6-P 1. Glc-6-P + 2NADP+  Ribulose-5-P + 2NADPH + CO2 2. Three steps ii. Isomerization and Epimerization reactins 1. 3 Ribulose-5-P  Ribose-5-P + 2 Xylulose-5-P iii. Carbon-Carbon cleavage/formation 1. 3C5  2C6 + C3 2. C6 = F-6-P 3. C3 = GAP 2. Understand the role of chlorophyll in reaction centers (bacterial and plant) and the surrounding membrane a. Role of chlorophyll in reaction centers i. Bacterial 1. Special pair of Chla and Chlb a. Absorbs light at 870 nm b. E- density localized over both rings 2. Bacteria pheophytin accepts electron from Chl special pair after absorption of photon 3. Transfers from bac pheophytin  menaquinone 4. Transfers from menaquinone  CoQ 5. Then back to reaction center after going through several cytochromes ii. Plant 1. Two reaction centers, takes 8 photons to produce 1 O2 2. DCMU blocks O2 evolution a. Blocks electron flow from PSII to cytochrome f 3. Derive electrons from H2O to reduce RC, then reduce NADP+ to NADPH 3. Understand in general terms the light and dark reactions, the products of each of these reactions, and overall products of photosynthesis in both bacteria and plants. a. Light reactions i. Photosystem II: 680 nm Chl special pair 1. Contains oxygen evolving complex (OEC) 2. 4 H+ released in thylakoid lumen (low pH in thylakoid lumen) 3. P680 passes electrons to CoQ and then to cytochrome bf complex, and then to PC 4. Product: a. 1/2O2 + 2H + 2PC ii. Photosystem I: 700 nm Chl special pair 1. Contains many proteins 2. Photon excites and becomes strong e- donor to ETC 3. P700+ accepts electrons from reduced PC 4. Electron passed to ferrodoxin, and then used to reduce NADP+ to NADPH 5. Products: a. NADPH + 2PC iii. Cyclic pathway: allows e- flow through PSI to drive PMF-ATP synthesis independent of reduction of NADP+ to NADPH and independent of oxidation of H2O to O2 1. Occurs when ratio of NADPH/NADP is high 2. Creates proton gradient to form ATP iv. Product of light reactions 1. O2 + 2NADPH + 3ATP b. Dark Reactions i. Use NADPH and ATP to fix and reduce CO2 to make hexose sugars ii. Calvin cycle: occurs in stroma iii. Steps: 1. Ribulose-1,5-BP + CO2  2 3PG a. Catalyzed by rubisco, does not use biotin 2. 3PG  1,3-BPG  GAP 3. Involves aldolases and transketolases iv. Product of dark reaction 1. Glc + 12NADP + 18ADP + 18 Pi c. Overall products of photosynthesis (in plants and bacteria) 4. Understand how photosynthesis is regulated in plants, light and dark reactions a. Light reactions i. Driven by absorption of photons b. Dark reactions i. Rubisco 1. Many plants synthesize rubisco inhibitor at night 2. CA1BP ii. pH of stroma increases due to light rxns 1. Rubisco had high pH optima 2. FBPase has high pH optima and is activated by NADPH which is a product of the light reactions 5. Understand the logic behind the calvin cycle, the overall reaction scheme, and how the cycle is regulated a. Logic: use NADPH and ribulose to produce hexose sugars b. Overall reaction scheme: i. Ribulose-1,5-BP  3-PC catalyzed by rubisco ii. Production of Fru-6-P from 3PG iii. Carbon-carbon rearrangements 1. Net Rxn: 5C3  3C5 6. Understand where the photon energy goes; PMF, NADP+ a. Cyclic pathway in PSI produces PMF when NADPH/NADP high b. PSI also can pass redox potential to NADP+ Fatty Acid Metabolism, Cholesterol Metabolism, and Their Regulation 1. Understand how TAGs are converted to free fatty acids and free fatty acids converted to mitochondrial acetyl-coA, as well as the role of carnitine a. How TAGs are converted to free fatty acids i. Occurs in adipocytes in low blood Glc ii. Glucagon binding stimulates HSL iii. HSL converts TAG to Glycerol and 3 fatty acids iv. Transported to liver by albumin 1. Free fatty acids have low solubility b. How free fatty acids are converted to mitochondrial acetyl-CoA i. Activation: 1. Fatty acyl-coA synthetae puts FA on acetyl-coA 2. Costs 2 ATP 3. Occurs in cytosol ii. Intracellular transport 1. Acyl group transferred to carnitine for transport to mito matrix 2. Carnitine palmitoyl transferases are bound to carnitine transporter 3. Carnitine carrier protein is an antiporter 4. The acyl group is then transferred from carnitine back to CoA 5. Acyl-CoA in matrix now ready for beta-oxidation iii. The role of carnitine 1. Transfers acyl group across IMM 2. Inhibited by malonyl-CoA in high blood Glc 2. Understand the steps in beta-oxidation and the production of FADH2 and NADH, as well as the compartmentalization of fatty acid oxidation and biosynthesis, and the role of carnitine palmitoyl transferase (CPT- 1) and the importance of its regulation by malonyl-coA a. Steps in beta-oxidation i. Acyl-CoA dehydrogenase with FAD 1. Chain length specificity 2. LCAD, MCAD, SCAD ii. H20 Addition iii. Oxidation iv. Acyl-coA DH FADH2 electron pair donated to CoQ of ETC v. 3 Steps: 1. Oxidation a. DH with FAD 2. H2O addition a. Hydratase 3. Oxidation a. DH with NAD+ vi. Compartmentalization of FA biosynthesis and oxidation 1. Oxidation in mito matrix: uses NAD 2. Synthesis in cytosol: uses NADP 3. Understand the regulation of fatty acid metabolism and its relationship with glucagon/insulin a. Glucagon activates HSL in adipocytes b. Malonyl-CoA inhibits CPT-1 in high blood Glc c. Acetyl-CoA carboxylase activated by insulin-dependent dephosphorylation and inhibited by glucagon-dependent phosphorylation and palmitoyl-coA d. Citrate shuttle: i. Acetate shuttled out of mito matrix as citrate ii. Citrate activates acetyl-coA carboxylase iii. Citrate only in cytosol during high blood glc e. Insulin stimulate synthesis and inhibits turnover of ACC and FAS f. Glucagon inhibits synthesis and stimulates turnover of ACC and FAS 4. Understand the HMG-CoA reductase reaction and acetyl-coA as the building block for cholesterol a. HMG-CoA reductase reaction i. HMG-CoA is formed from 3 Acetyl-coA ii. 2 NADPH per mevalonate 1. Mevalonate committed to cholesterol biosynthesis iii. Hydrolysis of thioester bond iv. Generation of primary alcohol v. Formation of isopentenyl pyrophosphate 1. Helps drive condensation of C5 units vi. Condensation of isopentenyl pyrophosphate: formation of squalene vii. Conversion of squalene to lanosterol 1. Cyclization of squalene by squalene epoxidase 2. To lanosterol: a. 14 NADPHs consumed viii. 19 step conversion of lanosterol to cholesterol 1. 15 NADPHs consumed 2. O2 consumed 5. Know how cholesterol levels are controlled (short and long term); hormonal and allosteric a. Control of HMG-CoA reductase i. Short term: 1. Allosteric a. Cholesterol b. CoQ c. Dolichol d. Farnesyl pyrophosphate e. Isopentenyl pyrophosphate 2. Regulation by phosphorylation: a. AMPK inactivates HMG-CoA reductase ii. Long term: 1. Cholesterol levels regulate a. Transcription of i. HMG-CoA reductase gene ii. HMG-CoA synthase gene iii. LDL receptor gene 2. Protein degradation of reductase a. Increase in [sterols] leads to degradation of HMG-coA reductase b. Low cholesterol: long-lived protein c. High cholesterol: short-lived protein b. Transcriptional Control of HMG-CoA Reductase i. SREBP 1. Regulates expression of: a. HMG-CoA synthase/reductase b. LDL receptor 2. Increased [cholesterol]  decreased txn of these genes 3. ER membrane protein must be cleaved by golgi membrane proteases to release SREBP txn factor a. SCAP has sterol sensing domain b. SCAP bound to cholesterol remains bound to Insig in ER ii. Cholesterol prevents proteolysis of SREBP by preventing SREBP from reaching the golgi apparatus where the proteases reside iii. When [cholesterol] drops, SREBP leaves the ER< tavels to the golgi and gets cleaved to release SREBP txn factor 6. Know the general features of apolipoproteins and their functions in lipoprotein particle function a. Features of apolipoproteins i. Promote cholesterol clearance ii. Surround amphipathic lipids, become water-soluble and can be transported iii. Highly alpha-helical secondary structure b. Functions in lipoprotein particle function i. Promote cholesterol clearance ii. Cofactor for enzymes 1. Activate or inhibit LCAT or LPL a. LCAT: transfers fatty acid from lecithin to cholesterol to produce cholesterol-ester b. LPL: cleaves fatty acids from TAGS in lipoprotein particles, delipidation iii. Ligands for cell-surface receptors iv. Increases cholesterol capacity in lipid particles c. VLDL, IDL, and LDL i. Distribute TAGs and cholesterol to peripheral tissues ii. VLDL: packaged and sent into the blood by liver cells 1. Particles are delipidated, they transition to IDL, and eventually LDL d. LDL Particles: i. Contain one copy of one protein Apo B-100 ii. ApoB-100 wraps around LDL particle iii. Phospholipid monolayer exterior 1. Because TAGs head groups in middle iv. TAGs and cholesterol esters inside 7. Understand generally how lipoproteins are packaged, as well as the role for chylomicrons, VLDL, IDL, LDL, and HDL in lipid transport, function, and homeostasis a. How lipoproteins are packaged: i. Intestinal cells create and package chylomicrons, which are then secreted to the blood ii. Chylomicrons are digested by LPL, which is activated by Apoprotein CII on the surface iii. Chylomicron remnants are taken up by liver cells iv. Liver cells produce and secrete VLDL into the blood (containing apob-100) v. LPL continually removes TAGs to create IDL, LDL, and HDL vi. Once LDL is endocytosed, and transferred to a lysosome, cholesterol is released and can be used for things such as membrane synthesis b. Role for chylomicrons, VLDL, IDL, LDL, and HDL in i. Lipid transport: 1. Allow water-insoluble lipids to travel through the blood ii. Lipid function: 1. Allows cholesterol derivatives to be transported to other places in the body, regulating cholesterol levels throughout iii. HDL: extracts cholesterol from plasma membranes of peripheral tissues 1. LCAT esterifies cholesterol in PM, cholesterol partitions to HDL particle from PM 2. Delivers cholesterol to IDL/LDL  liver  bile acids, then it is recycled 8. Understand the intracellular transport of the LDL receptor and the effects of FH mutations a. Intracellular transport of the LDL receptor i. Mediates uptake of LDL by endocytosis, binds ApoB100 ii. Binding in clathrin-coated pits; internalization; uncoating; pH drop by V-ATPase iii. LDL receptor returns to cell surface iv. LDL proceeds to lysosome b. Effects of FH mutations i. Can’t endocytose LDL particles from the blood ii. JD mutation defective in cytosolic domain Nitrogen and Nucleotide Metabolism 1. Understand the flux-control step, overall strategy, and regulation of the urea cycle a. Flux-control step: i. Urea cycle feeder reaction in mito matrix ii. Carbamoyl phosphate synthetase-1 (CPS-1) 1. 2 ATP + HCO3 + NH4  carbamoyl phosphate + 2ADP + Pi b. Overall strategy: i. Orthinine transcarbamoylase 1. Mito matrix 2. Orthinine + carbamoyl phosphate  Citrulline + Pi ii. Argininosuccinate synthetase 1. Cytosol 2. Citrulline + Aspartate + ATP  Argininosuccinate + AMP + PPi iii. Argininosuccinase 1. Cytosol 2. Argininosuccinate  arginine + fumarate iv. Arginase 1. Cytosol 2. Arginine + H2O  Orthinine + Urea c. Regulation of Urea cycle i. Regulated by substrate availability 1. Sources of free NH3 for cycle a. Oxidative deamination b. Glutamine hydrolysis ii. Allosteric activator of CPS-1: N-acetylglutamate 1. AA breakdown results in increase in [glutamate] which is used to make n-acetylglutamate 2. Know where the Ns, Cs, and Os come from to make carbamoyl phosphate for the urea cycle and nucleotide metabolism, know the role of carbamoyl phosphate synthetases in these pathways a. N’s i. Oxidative deamination ii. Glutamine hydrolysis b. CO2 from carbonate c. Role for carbamoyl phosphate synthetases in these pathways: i. Forms carbamoyl phosphate from HCO3 and NH4 using 2 ATP 3. Understand the aminotransferase reaction in amino-group exchange reactions, the function of the pyridoxal phosphate, and oxidative deamination of glutamate, and the production of free NH3, and the Glc- Ala cycle a. Aminotransferase reaction in amino-group exchange reactions i. NH2 group exchanged between amino acids and alpha-keto acids ii. Mechanism 1. NH2 transferred to the enzyme 2. Alpha-keto acid leaves active site 3. Enzyme-NH2 transfers NH2 to incoming alpha-keto acid 4. Amino acid product leaves b. Function of pyridoxal phosphate i. PLP is phosphorylated and oxidized to the aldehyde ii. Adelhyde is reactive portion of PLP iii. PLP forms covalent shiff base adduct with enzyme Lys amino group iv. PLP remains bound at enzyme active site during entire rxn cycle v. Role in transaminations 1. Incoming aa donates NH2 to PLP to form PMP 2. PMP stays bound at active site 3. Alpha-keto acid dissociates from enzyme 4. New a-keto acid binds active site, picks up NH2 group 5. Second aa leaves c. Oxidative deamination of glutamate i. Glutamate + NADP + H20  alpha-ketoglutarate + NH4 + NADPH ii. Enzyme: glutamate dehydrogenase d. Glc-Ala cycle i. Degradation of amino acids for fuel yields NH3 ii. Nitrogen can only be converted to urea by liver cells iii. NH3 delivered to liver cells through the blood as alanine iv. Alanine is NH3 carrier v. Under fasting conditions 1. Connects muscle to liver 2. Most of C skeleton comes from aa in muscles 4. Understand generally the de novo and salvage pathways for purine and pyrimidine biosynthesis pathways, the different synthetic strategies for each, and the flux controlling steps and their regulation a. Purine i. De novo 1. Starts with Ribose-5-P from PPP 2. ATP is used to add pyrophosphate (PPi) to ribose-5-P to form the high energy intermediate PRPP 3. Amino group added to C1a position of PRPP 4. Then glycine is added to the B-NH2 in an ATP- dependent reaction 5. Biosynthesis of IMP a. Purine ring synthesized attached to ribose ring b. Progressive addition of carbon and nitrogen c. 11 steps from ribose-5-p to IMP d. N -Formyl-THF i. 1 carbon additions e. Second NH group from glutamine 6. Regulation: a. Flux control: R5P to PRPP i. Inhibited by GDP and ADP b. PRPP committed to nucleotide biosynthesis c. PRPP to 5-phosphoribosylamine is inhibited by AMP/ADP/GMP/GDP and activated by PRPP i. Feed forward activation ii. Committed to purine biosynthesis ii. Salvage 1. Free purine bases (no ribose attached) can be directly attached to PRPP to form the XMP nucleotides 2. APRT a. Adenine + PRPP  AMP + PPi 3. HGPRT a. Hypoxanthine + PRPP  IMP + PPi b. Guanine + PRPP  GMP + PPi 4. Non-dividing cells use salvage pathway b. Pyrimidine i. De novo 1. Build ring and then put on ribose 2. Synthesized de novo from carbamoyl phosphate and aspartate 3. Carbamoyl phosphate synthetase II a. Catalyzes production of cytoplasmic carbamoyl phosphate b. Uses glutamine c. Flux control step: activated by PRPP d. UDP/UTP feedback inhibition 4. Ribose sugar added after ring formation as PRPP 5. UMP synthesized first  UTP, CTP ii. Salvage 1. Salvage of free pyrimidine bases 2. Uracil + PRPP  UMP + PPi 5. Understand the conversion of NDPs to dNDPs, and the role of NADPH as a reductant a. Conversion of NDPs to dNDP i. Ribonucleotide reductases convert riboNDPs to dNDPs 1. Use NADPH as reductant 2. Form dADP, dCDP, dGDP, and dUDP 3. Then dNDP + ATP  dNTP + ADP 4. dUTP + H20  dUMP + PPi 5. dUMP  dTMP a. Thymidylate synthase adds methyl group from 5 10 N , N -Methylene THF to dUMP b. Role of NADPH as a reductant i. Cofactor for ribonucleotide reductase 6. Understand the formation of dTMP using N ,N -Methylene THF, and the logic of the THF regeneration cycle as a major target of drugs that prevent cell proliferation a. Formation of dTMP using N ,N -Methylene THF i. Thymidylate synthase adds methyl group from N ,N - 10 Methylene THF to dUMP ii. dUMP  dTMP 1. [dUTP] kept low because it cannot be distinguished from dTTP and is mutagenic if incorporated b. Logic of THF regeneration cycle i. Two step cycle ii. Needed for DNA synthesis iii. Rapidly growing cells need lots of dUMP  dTMP iv. DHFR re-reduces THF 5 10 v. Serine hydroxymethyl transferase adds N ,N -Methylene group onto THF c. As a major target of drugs that prevent cell proliferation i. N ,N -Methylene THF catalyzes the conversion of dUMP  dTMP which is important for proliferating cells to use in DNA synthesis ii. By inhibiting this cycle, N ,N -Methylene THF is no longer able to be regenerated, therefore halting cell division 7. Understand the production of uric acid as the end product of purine degradation, circumstances that lead to overproduction of purines, and the outcomes of excess accumulation of uric acid a. Uric acid as the end product of purine degradation i. Purines converted to xanthine and then uric acid b. Circumstances that lead to overproduction of purines i. Lack of inhibition of flux control step in purine synthesis? ii. No inhibition of PRPP c. Outcomes of excess accumulation of uric acid i. Gout 1. Formation of insoluble crystal in joints of extremities 2. Treated by inhibiting the transition of xanthine to uric acid by binding to xanthine Metabolism Overview, Proliferative Metabolism, and Diseases of Metabolism 1. Understand the roles of the liver, muscle, and adipose tissue in blood glucose level homeostasis a. Liver: i. Low blood glucose: I Glucagon/epinepherine 1. Glycolysis 2. Gluconeogenesis 3. Glut2 is transporting glucose out of the liver ii. High blood glucose: Insulin 1. Glycogen synthesis 2. Lipid synthesis 3. Glut2 transporting glucose into liver b. Muscle cells: i. Low blood Glc: Epinepherine 1. Glycolysis ii. High blood Glc: Insulin 1. Glycogen synthesis 2. Glut4 receptors transported to PM c. Adipose tissue: i. Low blood Glc: Glucagon 1. Lipid metabolism to transport fatty acids ii. High blood Glc: Insulin 1. Lipid synthesis 2. Glut4 receptors transported to PM 2. Know which organs/cells store/produce/utilize fatty acids, ketone bodies, and glucose a. Fatty acids: i. Stored in adipose cells ii. Produced in the liver and adipose tissue iii. Utilized by liver and muscle b. Ketone bodies: i. Stored in ??? ii. Produced in liver iii. Utilized in liver, brain, muscle, kidney c. Glucose: i. Stored as glycogen in liver and muscle, stored as TAGs in adipose tissue ii. Produced in liver and muscle iii. Utilized in liver, muscle, kidney, and adipose tissue 3. Know which cells store glycogen and the eventual fate of glycogen in those cells a. Liver cells i. Used for glycolysis, and PPP by converting through the HMP b. Muscle cells i. Used for glycolysis 4. Know the conditions that favor the production of insulin/glucagon/epinephrine, and how liver, muscle, and adipose cells respond to each of these hormones. a. Insulin: i. Favored in high blood glucose (well fed) ii. Liver: 1. More Glc uptake by Glut2 2. Glycogen synthesis 3. Lipid synthesis on iii. Muscle: 1. More Glc uptake by Glut4 2. Glycogen synthesis 3. High LPL activity iv. Adipose cells: 1. Lipid synthesis (high LPL activity) 2. HSL low 3. Increase of Glut4 at PM b. Epinephrine/Glucagon: i. Favored in low blood Glc (fasting) ii. Liver: 1. Glycolysis off 2. Gluconeogenesis high 3. Pyruvate kinase phosphorylated, inactivated iii. Muscle: 1. Proteins made into amino acids a. Transported to liver through Ala/Gln 2. Glc  lactate, although not dependent on blood glc level 3. Low Glc uptake 4. LPL activity low iv. Adipose cells: 1. HSL activity high: TAGS  Fatty acid + glycerol  blood 2. Low Glc uptake 3. LPL activity low 5. Understand the metabolic imbalances that result from diabetes, the mechanisms by which insulin regulates blood glucose levels, and what goes wrong in the different forms of diabetes a. Understand the metabolic imbalances that result from diabetes i. Type I 1. No insulin produced 2. Stuck in fasting phase with gluconeogenesis even in high Glc 3. Liver sends Glc to blood even in high blood Glc (hyperglycemia) 4. Fat cells liberate large quantities of fatty acids 5. TAGs accumulate in the blood a. Insulin needed to stimulate LPL, do not get broken down and cannot be transported ii. Type II 1. Early stages: both insulin and blood Glc levels are elevated 2. Later stages: insulin levels reduced, blood Glc levels very elevated 3. Insulin resistant tissues, sometimes fewer insulin receptors on PM 4. Tissues less responsive to insulin 5. Elevated blood Glc due to: a. Muscle/Fat: low level recruitment of Glut4 to PM b. Liver: Gluconeogenesis not turned off in high blood Glc i. Low Fru-2,6-BP levels due to PPP-1 ii. PPP-1 activated by insulin b. Mechanisms by which insulin regulates blood glucose levels i. Insulin stimulates glycogen synthesis in liver and muscle cells in high blood Glc ii. Shuts down gluconeogenesis in the liver iii. Increased uptake by Glut4 in muscle and adipose cells iv. Glycolysis turned on in liver cells 6. Understand the role of AMPK in sensing/regulating cellular energy status, and the key enzymes/pathways effected by AMPK, particularly in those affected by diabetes a. Role of AMPK in sensing/regulating cellular energy status i. Tumor suppressor and regulates cellular metabolism ii. AMP activates AMPK, AMPK responds to ATP/AMP ratio iii. AMPK inhibits anabolic pathways and activates catabolic pathways to reestablish high ATP/ADP ratio iv. AMPK inhibits: 1. ACC2: creates lower levels of malonyl-coA a. ACC2 inhibits FA oxidation in non-liver cells 2. HMG reductase: cholesterol synthesis 3. ACC1/FAS: fatty acid synthesis 4. Gluconeogenesis: PEPCK/G6Pase 5. Glycogen synthesis: glycogen synthase v. AMPK activates: 1. Glut4 to PM in muscle and fat cells 2. Fatty acid oxidation 3. PFK-2 in cardiac muscle vi. AMPK controls cell proliferation and defects in AMPK promote cell proliferation vii. AMPK down regulates selenoprotein P 7. Understand the big picture differences between proliferative metabolism and quiescent cell metabolism a. Proliferative metabolism i. Glucose  pyruvate  lactate ii. Aerobic glycolysis iii. Anabolic pathways needed: 1. FA/cholesterol synthesis 2. AA/protein synthesis 3. NADPH production iv. Needs of proliferating cell 1. Glucose 2. Glutamine 3. Oxygen 4. M2 isoform PK v. Glutaminolysis: provides NH3 and carbon for AA, nucleotides 1. Anaplerotic 2. Gln/AAs used in nucleotide de novo pathways b. Quiescent cell metabolism i. Anaerobic glycolysis 1. Glc  pyruvate  lactate ii. Oxidative phosphorylation 1. Glc  pyruvate  CO2 8. Understand generally hormone regulation of metabolism: insulin, glucagon, epinephrine, leptin, GLP-1, NPY, PYY, Ghrelin, SeP, Irisn a. Leptin i. Appetite control ii. Leptin injections in ob/ob mice caused weight loss iii. Receptor expressed in blood/brain barriet but also expressed in muscle/fat etc. b. GLP-1 i. Appetite suppresent ii. Stimulates thermogenesis in adipose tissue c. NPY i. Appetite stimulant d. PYY i. Produced by intestine, potent appetite suppressant ii. Competes for same receptor as NPY causes a decrease in secretion of NPY and AgRP e. Ghrelin i. Produced by stomach ii. Appetite stimulator f. SeP g. Irisn i. Secreted into blood by muscle tissue due to exercise ii. Causes adipose tissue to express UCP1: causes white adipose to develop much like BAT iii. Increases thermogenesis 9. Know the difference between functional and positional cloning, the factors that limit the use of each cloning approach, how one determines whether the identified mutation is the cause of a genetic disease (FH, CF, and OB examples), and understand the importance of the functional test and what it is a. Functional vs. positional cloning i. Functional cloning: 1. Uses a known gene sequence as a probe to look for new gene sequences that may have similar functions 2. Can search entire genome without having prior


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